Data generated by the investigators in this program project grant and others indicate that gamma-secretase[unreadable] inhibitors (GSIs) may be useful drugs in such diverse settings Alzheimer's Disease (AD), cancer, multiple[unreadable] sclerosis, and immune rejection, and that the adverse effects caused by GSIs are not insurmountable. We will[unreadable] use GSIs as tools to explore the therapeutic potential of targeting gamma-secretase in vivo. In the context of this[unreadable] program project the main goal of the chemistry core will be to synthesize sufficient GSI to support the[unreadable] studies in Projects 1-3 and develop methods to measure GSI levels in body fluids and tissues following in[unreadable] vivo dosing.[unreadable] The aims of the Chemistry Core are:[unreadable] Aim 1. To synthesize all four L-alanine-containing enatiomerically pure diastereomers of LY-411,575, an[unreadable] extremely potent gamma-secretase inhibitor (GSI), and to isolate large quantities of the most potent diastereomer of[unreadable] LY-411,575 for in vivo studies.[unreadable] Aim 2. To develop a reliable method of qualitative and quantitative analysis of LY-411,575 stereoisomers[unreadable] and related analytes and metabolites in biological fluids and tissues.[unreadable] Aim 3. To synthesize other GSIs required for the studies proposed in projects 1-3.